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  • 1
    Digitale Medien
    Digitale Medien
    Release of endogenous GABA from the substantia nigra is not controlled by GABA autoreceptors (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 340 (1989), S. 372-378 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; Electrical/K+ stimulation ; Substantia nigra slices ; Baclofen ; Muscimol ; Bicuculline
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The characteristics of the release of GABA from slices of the rat substantia nigra, elicited by electrical stimulation at frequencies of 0.5–48 Hz and by elevated K+ concentrations ranging from 15–35 mmol/l, was studied. Comparisons were made with cortical slices where the data were not available from previous studies. No GABA release could be evoked from rat nigral slices by electrical stimulation between 0.5 and 4 Hz, in contrast to cortical slices, in which this pool is sensitive towards inhibition by (−)-baclofen. Also, comparatively less GABA release could be evoked from nigral than from cortical slices by K+ concentrations between 15 and 25 mmol/l. While (−)-baclofen at 10 μmol/l inhibited release caused by 15 μmol/l K+ in cortical, it did not in nigral slices. GABA release caused by higher frequencies (8–48 Hz) or 30 mmol/l K+ concentrations was Ca2+-dependent and in the former case also tetrodotoxin-sensitive. It had similar characteristics as in cortical slices and was insensitive towards (−)-baclofen, muscimol and bicuculline. Even more markedly than in the cortex, 30 mmol/l K+ released greater amounts of GABA than electrical stimulation at 24 Hz of a similar duration, suggesting the existence of one or several additional pool(s) of lesser excitability. Since the majority of gabaergic nerve endings in the nigra belong to striato- and pallidonigral projection neurons and those in the cortex probably exclusively to various types of interneurons, it seems that (a) one or several of the latter release GABA at low frequencies in a baclofen-sensitive manner and are absent or rare in the s. nigra, and (b) the striato- and pallidonigral projection neurons are not controlled by presynaptic autoreceptors of the GABAA or GABAB type, because neither GABA release elicited by electrical stimulation nor by 30 mmol/l K+ was affected by agents interfering with these types of receptors.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00167037
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  • 2
    Digitale Medien
    Digitale Medien
    Potential involvement of a baclofen-sensitive autoreceptor in the modulation of the release of endogenous GABA from rat brain slices in vitro (1988)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 337 (1988), S. 289-295 
    Details
    ISSN: 1432-1912
    Schlagwort(e): Baclofen ; GABA release ; Brain slices ; Muscimol ; Bicuculline
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The effects of the GABAA agonist, muscimol, and of the enantiomers of the GABAB agonist, baclofen, on the release of endogenous GABA from slices of the rat cerebral cortex, striatum and hippocampus were measured by means of a HPLC method with electrochemical detection. Moreover, the effect of the GABAA antagonist, bicuculline, and of the frequency of stimulation were studied in cortical slices. The amount of endogenous GABA released per impulse from cortical slices decreased by about 50% when the frequency was increased from 0.25 Hz to 1 Hz. This might indicate that GABA inhibited its own release. (−)-Baclofen at 1 and 10 μM, but not its (+)-enantiomer, markedly inhibited the release of endogenous GABA, to a similar extent in all 3 areas investigated. The effect of (−)-baclofen was dependent on the frequency of stimulation: at lower frequencies (0.25 and 0.5 Hz) it was more marked than at a higher one (4 Hz). This would be expected from the results showing that the release of endogenous GABA decreases with increasing frequency, which suggests that this amino acid inhibits its own release. Muscimol at 10 μM, on the other hand, was ineffective in all 3 areas at a stimulation frequency of 0.5 Hz. Bicuculline (10 μM) at 4 Hz, at which autosuppression of GABA release is maximal did not enhance the release of endogenous GABA from cortical slices. With cerebellar or nigral slices, no adequate stimulation-induced release of endogenous GABA could be obtained under comparable conditions. These data are compatible with, but do not prove the existence of GABAB-type presynaptic autoreceptors modulating the release of this amino acid. More definite conclusions may possibly be drawn when a GABAB antagonist becomes available, which is expected to enhance GABA release under appropriate conditions.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00168841
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  • 3
    Digitale Medien
    Digitale Medien
    Ca2+-dependent release of endogenous GABA from rat cortical slices from different pools by different stimulation conditions (1989)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 339 (1989), S. 200-207 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; K+-Stimulation ; Electrical stimulation ; Brain slices ; Glutamate effect ; Baclofen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The previously reported inhibitory effect of (−)-baclofen on the electrically evoked release of endogenous GABA from rat brain slices indicated the possibility of existence of GABAB autoreceptors. In this study, we have tested an alternative explanation, i. e. the possibility that (−)-baclofen reduced an excitatory glutamatergic input to GABAergic neurons by inhibiting glutamate release, by investigating the interaction of 10 mmol/1 l-glutamate with the inhibitory effect of 10 μmol/1(−)-baclofen. l-Glutamate did not affect the electrically evoked release of GABA on its own and did not abolish the effect of (−)-baclofen, suggesting that the latter was not secondary to a reduction of glutamate release. On the other hand, it greatly increased the basal release of GABA and more than doubled the GABA content of the slices at the end of the perfusion, indicating a marked enhancement of GABA synthesis. This additional GABA, apparently formed from exogenous l-glutamate, was not releasable by electrical stimulation at 0.5 or 24 Hz, but at least in part by stimulation with 30 mmol/l K+. The previously reported increase of GABA release at 12 Hz as compared to 4 Hz was studied in more detail. GABA released by electrical stimulation at 8–48 Hz was Ca2+-dependent and tetrodotoxin-sensitive. No evidence was obtained for a decrease of the amount of GABA released per impulse with increasing frequency in this range. Moreover, neither (−)-baclofen nor muscimol at 10 μmol/l altered the release of the amino acid at 24 Hz; the former was also tested at a low Ca2+ concentration (0.3 mmol/l) and found to be inactive under these conditions. Thirty mmol/l K+ released about 30% higher amounts of GABA than electrical stimulation at 24 Hz under comparable conditions, in a Ca2+-dependent manner. K+-induced release was not modified by 10 μmol/l (−)-baclofen or muscimol. Our results suggest the existence of at least 2 different, presumably neuronally located, releasable pools of GABA. One is sensitive to electrical stimulation at 0.25–4 Hz and responds to (−)-baclofen, suggesting control by GABAB-type autoreceptors. The existence of a 2nd pool is indicated by the fact that K+ releases substantially more GABA than electrical stimulation and by the exclusive sensitivity of K+-evoked GABA release to exogenous l-glutamate. GABA released by electrical stimulation at frequencies above 4 Hz may come from a 3rd pool. Both the 2nd and the 3rd pool seem to be insensitive to (−)-baclofen and muscimol.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00165144
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  • 4
    Digitale Medien
    Digitale Medien
    Investigations on GABAB receptor-mediated autoinhibition of GABA release (1990)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 341 (1990), S. 88-93 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; Electrical stimulation ; Cortex slices ; GABAB autoreceptor ; Baclofen ; Phaclofen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary In this study, we have investigated the effects of phaclofen on the [3H] overflow from [3H]GABA prelabelled rat cortical slices and its interaction with the effects of (−)-baclofen in dependence of the stimulation frequency. (−)-Baclofen strongly depressed the [3H] overflow in the frequency range of 0.125 to 4 Hz to a constant residual level (ICIn50 = 0.37 μmol/l at 0.125 Hz), but became inactive above. The potency of the (+)-enantiomer was considerably weaker by a factor of nearly 1000. The GABAB antagonist, phaclofen, increased [3H] overflow at 300 μmol/l and, moremarkedly, at 3 and 1 mmol/l, respectively. However, the increase was virtually independent of the frequency between 0.125 and 16 Hz. If the compound interacted only with the putative GABAB autoreceptor involved in the regulation of GABA release, the extent of the enhancing effect should increase with increasing frequency because of the concomitant rise in synaptic GABA concentration. In order to further investigate this phenomenon, the IC50 of (−)-baclofen and antagonism of phaclofen against (−)-baclofen were determined at 0.125 Hz and 2 Hz, respectively. Whereas the IC50 of (−)-baclofen was 0.63 ± 0.04 μmol/l at 0.125 Hz, it increased to 4.88 + 0.45 μmol/l at 2 Hz. The pA10-values of phaclofen were about the same at both frequencies, whereas the pA2-values differed by a factor of 2.3. Therefore, the possibility should be considered that (−)-baclofen does not only interact with presynaptic GABA autoreceptors, but also may interact with other - presumably somatodendritic- GABAB-receptors whose pharmacology is not identical with that of the receptors by which (−)-baclofen exerts its effects on GABA release.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00195063
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  • 5
    Digitale Medien
    Digitale Medien
    A role for computer simulation in solving the riddles of autoreceptor-mediated regulation of GABA release (1993)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 348 (1993), S. 618-627 
    Details
    ISSN: 1432-1912
    Schlagwort(e): GABA release ; Autoreceptor ; GABA uptake ; computer simulation ; GABAB antagonists ; Baclofen
    Quelle: Springer Online Journal Archives 1860-2000
    Thema: Medizin
    Notizen: Summary The autoreceptor-mediated control of GABA release was simulated on a personal computer using commercially available software (STELLATM/ITHINKTM). The experimental data to be matched were taken from previous publications. A basic model was able to fairly accurately reproduce frequency dependencies of GABA release in the presence and absence of uptake inhibition as well as concentration-response curves for changes in release produced by the agonist, (−)-baclofen, or by relatively low concentrations of the antagonists, phaclofen and CGP 35348. Obvious mismatch was observed at high concentrations of a potent antagonist, at a stimulation frequency of 2 Hz. Whereas the experimental data indicate a 3-fold increase in release as compared to controls, simulation predicts a 7-fold increase. By adaptation of the model, simulation data were obtained indicating that this mismatch was not due to (a) the autoreceptor occurring as two subtypes with different affinities for antagonists, (b) the occurrence of an agonist and antagonist state of the autoreceptor, with the latter prevailing at low synaptic concentrations of endogenous GABA, and (c) overruling of uptake inhibition by markedly elevated synaptic GABA concentrations. On the other hand, a simple restriction of the amount of transmitter able to be released per time unit produced much better matching data. A refined model assuming a restricted replacement capacity for exocytotically emptied synaptic vesicles at their docking sites gave similar results. As a consequence, we shall attempt to address this possibility experimentally. Simulation can never prove a case in the positive sense. It can, however, help to exclude ill-matching solutions of a problem and to prioritize among possible ones, which then must be experimentally addressed. We found simulation with this user-friendly software extraordinarily useful, also and not least because it necessitates and stimulates very intense dealing with a subject.
    Materialart: Digitale Medien
    URL: http://dx.doi.org/10.1007/BF00167238
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